As the most abundant white blood cells in humans, neutrophils play a key role in acute and chronic inflammation, suggesting that these cells are a key component of targeted therapies for various inflammation-related diseases. Specific enzyme-responsive or specific ligand-modified polymer nanoparticles are beneficial for improving drug efficacy, reducing toxicity, and enhancing focal site retention. However, there remain significant challenges in biomedical applications of these synthetic polymer nanoparticles, mainly due to their rapid clearance by the reticuloendothelial system. In recent years, biomimetic drug delivery systems such as neutrophils acting directly as drug carriers or neutrophil-membrane-coated nanoparticles have received increasing attention due to the natural advantages of neutrophils. Thus, neutrophil-targeted, neutrophil-assisted, or neutrophil-coated nanoparticles exhibit a prolonged blood circulation time and improved accumulation at the site of inflammation. Despite recent advancements, further clinical research must be performed to evaluate neutrophil-based delivery systems for future biomedical application in the diagnosis and treatment of related inflammatory diseases. In this review, we have summarized new exciting developments and challenges in neutrophil-mediated drug delivery strategies for treating inflammation-related diseases.

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases. However, effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases. Herein we report a novel strategy for engineering inflammation-accumulation nanoparticles via phenolic functionalization. Different phenol-functionalized nanoparticles were first developed, which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment. Phenolic compound-decorated poly (lactide-co-glycolide) nanoparticles, in particular tyramine (Tyr)-coated nanoparticles, showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis, acute liver injury, and acute lung injury, mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species. By combining a cyclodextrin-derived bioactive material with Tyr decoration, a multifunctional nanotherapy (TTN) was further developed, which displayed enhanced cellular uptake, anti-inflammatory activities, and inflammatory tissue accumulation, thereby affording amplified therapeutic effects in mice with colitis or acute liver injury. Moreover, TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration, leading to considerably potentiated in vivo efficacies. Preliminary studies also revealed good safety of orally delivered TTN. Consequently, Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.